Assessing bacterial prevalence and resistance in paediatric meningitis: safeguarding the central nervous system.

Introduction: Paediatric bacterial meningitis (PBM) represents a major contributor to childhood morbidity and mortality globally, with heightened susceptibility in low- and middle-income nations where antimicrobial resistance (AMR) is highly prevalent. Pakistan exemplifies this setting, with widespread antibiotic overuse driving AMR expansion. Thus, expediting PBM diagnosis and targeted antibiotic therapy is imperative yet challenged by the dynamic local epidemiology. This study aimed to delineate the recent bacterial etiologies and AMR profiles of PBM from a major Pakistani diagnostics laboratory to inform empirical treatment. Materials and methods: This prospective observational investigation evaluated PBM epidemiology in patients under 18 years old admitted to the study hospital. Standard cerebrospinal fluid analysis identified bacterial pathogens and antibiotic susceptibility patterns. Results: Among 171 PBM cases, 152 (88.9%) had bacterial isolates confirmed via culture. The cohort was 42.7% male with a mean age of 3 months. The most prevalent pathogens among infants younger than 3 months were Escherichia coli, Enterococcus faecium, and Staphylococcus epidermidis, contrasting with S. epidermidis, Streptococcus pneumoniae, and Staphylococcus hominis predominating in older children. Staphylococcal isolates exhibited considerable penicillin and erythromycin resistance but maintained vancomycin and linezolid susceptibility. Other resistance patterns varied. Conclusion: These findings highlight the pressing threat of paediatric AMR in Pakistan, underscoring the need for vigilant AMR surveillance and judicious antimicrobial use. This study provides a reference to current PBM epidemiology to guide context-specific empirical therapy.

Magnetoelectric core-shell CoFe2O4@BaTiO3 nanorods: their role in drug delivery and effect on multidrug resistance pump activity in vitro.

Nanoparticle mediated targeted drug delivery has become a widespread area of cancer research to address premature drug delivery problems. We report the synthesis of magneto-electric (ME) core-shell cobalt ferrite-barium titanate nanorods (CFO@BTO NRs) to achieve "on demand" drug release in vitro. Physical characterizations confirmed the formation of pure CFO@BTO NRs with appropriate magnetic and ferroelectric response, favorable for an externally controlled drug delivery system. Functionalization of NRs with doxorubicin (DOX) and methotrexate (MTX) achieved up to 98% drug release in 20 minutes, under a 4 mT magnetic field (MF). We observed strong MF and dose dependent cytotoxic response in HepG2 and HT144 cells and 3D spheroid models (p < 0.05). Cytotoxicity was characterized by enhanced oxidative stress, causing p53 mediated cell cycle arrest, DNA damage and cellular apoptosis via downregulation of Bcl-2 expression. In addition, MF and dose dependent inhibition of Multidrug Resistance (MDR) pump activity was also observed (p < 0.05) indicating effectivity in chemo-resistant cancers. Hence, CFO@BTO NRs represent an efficient carrier system for controlled drug delivery in cancer nanotherapeutics, where higher drug uptake is a prerequisite for effective treatment.

Biocompatibility and cytotoxicity in vitro of surface-functionalized drug-loaded spinel ferrite nanoparticles.

In this study, poly(isobutylene-alt-maleic anhydride) (PMA)-coated spinel ferrite (MFe2O4, where M = Fe, Co, Ni, or Zn) nanoparticles (NPs) were developed as carriers of the anticancer drugs doxorubicin (DOX) and methotrexate (MTX). Physical characterizations confirmed the formation of pure cubic structures (14-22 nm) with magnetic properties. Drug-loaded NPs exhibited tumor specificity with significantly higher (p < 0.005) drug release in an acidic environment (pH 5.5). The nanoparticles were highly colloidal (zeta potential = -35 to -26 mV) in deionized water, phosphate buffer saline (PBS), and sodium borate buffer (SBB). They showed elevated and dose-dependent cytotoxicity in vitro compared to free drug controls. The IC50 values ranged from 0.81 to 3.97 µg/mL for HepG2 and HT144 cells, whereas IC50 values for normal lymphocytes were 10 to 35 times higher (18.35-43.04 µg/mL). Cobalt ferrite (CFO) and zinc ferrite (ZFO) NPs were highly genotoxic (p < 0.05) in cancer cell lines. The nanoparticles caused cytotoxicity via oxidative stress, causing DNA damage and activation of p53-mediated cell cycle arrest (significantly elevated expression, p < 0.005, majorly G1 and G2/M arrest) and apoptosis. Cytotoxicity testing in 3D spheroids showed significant (p < 0.05) reduction in spheroid diameter and up to 74 ± 8.9% of cell death after two weeks. In addition, they also inhibited multidrug resistance (MDR) pump activity in both cell lines suggesting effectivity in MDR cancers. Among the tested MFe2O4 NPs, CFO nanocarriers were the most favorable for targeted cancer therapy due to excellent magnetic, colloidal, cytotoxic, and biocompatible aspects. However, detailed mechanistic, in vivo cytotoxicity, and magnetic-field-assisted studies are required to fully exploit these nanocarriers in therapeutic applications.

Cyperus spp.: A Review on Phytochemical Composition, Biological Activity, and Health-Promoting Effects.

Cyperaceae are a plant family of grass-like monocots, comprising 5600 species with a cosmopolitan distribution in temperate and tropical regions. Phytochemically, Cyperus is one of the most promising health supplementing genera of the Cyperaceae family, housing ≈950 species, with Cyperus rotundus L. being the most reported species in pharmacological studies. The traditional uses of Cyperus spp. have been reported against various diseases, viz., gastrointestinal and respiratory affections, blood disorders, menstrual irregularities, and inflammatory diseases. Cyperus spp. are known to contain a plethora of bioactive compounds such as α-cyperone, α-corymbolol, α-pinene, caryophyllene oxide, cyperotundone, germacrene D, mustakone, and zierone, which impart pharmacological properties to its extract. Therefore, Cyperus sp. extracts were preclinically studied and reported to possess antioxidant, anti-inflammatory, antimicrobial, anticancer, neuroprotective, antidepressive, antiarthritic, antiobesity, vasodilator, spasmolytic, bronchodilator, and estrogenic biofunctionalities. Nonetheless, conclusive evidence is still sparse regarding its clinical applications on human diseases. Further studies focused on toxicity data and risk assessment are needed to elucidate its safe and effective application. Moreover, detailed structure-activity studies also need time to explore the candidature of Cyperus-derived phytochemicals as upcoming drugs in pharmaceuticals.

Haplotype comparisons of Echinococcus granulosus sensu lato via mitochondrial gene sequences (co1, cytb, nadh1) among Pakistan and its neighbouring countries.

Echinococcus granulosus sensu lato (s.l.) is a zoonotic parasite that causes cystic echinococcosis (CE) in humans. However, E. granulosus sensu stricto (s.s.) is considered the predominant species in CE infections worldwide. According to the population genetic diversity and structure of E. granulosus s.l., gene flow can explain the parasite drift among the neighbouring countries of Pakistan. The mitochondrial (mt) co1 (n = 47), nadh1 (n = 37) and cytb (n = 35) nucleotide sequences of E. granulosus s.l. isolates from Pakistan, Iran, China and India were retrieved from the National Centre for Biotechnology Information database to determine the genealogical relationships. The sequences were grouped as the mt-co1 (genotypes G1 and G3, G6-G7), mt-cytb (genotypes G1 and G3), and mt-nadh1(genotypes G1 and G3). The data were analysed using bioinformatic tools. A total of 19 polymorphic sites for the mt-co1 sequence (374 bp) were observed of which 31.6% (6/19) were parsimony-informative sites. Unique singleton haplotypes within the E. granulosus s.s. haplotype network based on the mt-co1 gene were highly prevalent (68.4%; 13/19) in Pakistani isolates followed by Chinese, Indian and Iranian isolates; four polymorphic sites were detected in the E. canadensis (G6/G7). In E. canadensis mt-co1 haplotype network, 75% (3/4) unique singleton haplotypes were from the Iranian isolates. Twelve polymorphic sites were found using the mt-cytb sequence (547 bp); 25% (3/12) were parsimony-informative and there were 66.7% (8/12) unique singleton haplotypes within the mt-cytb haplotype network in E. granulosus s.s. with the most reported from Pakistan followed by Iran and China. 20 polymorphic sites were detected in E. granulosus s.s. mt-nadh1 sequences (743 bp); 20% (4/20) were parsimony-informative. There were 66.7% (8/12) main single haplotypes within the mt-nadh1 haplotype network, with the most reported from Pakistan followed by that from India, Iran and China. The sequence analyses show low nucleotide diversity and high haplotype diversity in general.

Field-controlled magnetoelectric core-shell CoFe2O4@BaTiO3 nanoparticles as effective drug carriers and drug release in vitro.

The targeted drug release at tumor cells while sparing normal cells is a huge challenge. Core-shell magnetoelectric (ME) nanoparticles have addressed this problem using shape-dependent magneto-electric attributes. The colloidally stable, core-shell cobalt ferrite@barium titanate (CFO@BTO) ME nanoparticles (NPs) used for in vitro study were synthesized using sonochemical method. The structural characteristics and core-shell morphology were analyzed by X-ray Diffraction (XRD) and Transmission Electron Microscopy (TEM) respectively. Further magnetic and exchange coupling between two phases of ME nanostructures were studied at room temperature. Colloidal stability was studied in different suspension solutions (Water, SBB, PBS, and DMEM) using dynamic light scattering. Subsequently, the synthesized nanoparticles were functionalized with anticancer drugs including doxorubicin and methotrexate up to 80% via (EDC) chemistry. In vitro cytotoxicity studies carried out on human hepatocellular carcinoma (HepG2) and human malignant melanoma (HT144), cells validated the magneto-electric property of CFO@BTO nano-carriers in the presence of external magnetic field (5 mT), with significantly enhanced cytotoxicity when compared to free drugs and without field replicates. The resulted IC50 values ranging from 5.3-7.3 µg/ml compared to 30.1-43.1 µg/ml in the absence of a magnetic field also confirmed the involved physical attributes of magnetoelectric nanostructures. The fluorescent microscopy results also indicated the increased apoptosis in magnetic field-assisted samples. Finally, hemolysis assay indicated the suitability of CFO@BTO nano-carriers for intravenous applications at IC50 concentration.

Corrosion and Heat Treatment Study of Electroless NiP-Ti Nanocomposite Coatings Deposited on HSLA Steel.

Corrosion and heat treatment studies are essential to predict the performance and sustainability of the coatings in harsh environments, such as the oil and gas industries. In this study, nickel phosphorus (NiP)-titanium (Ti) nanocomposite coatings (NiP-Ti nanoparticles (TNPs)), containing various concentrations of Ti nanoparticles (TNPs) were deposited on high strength low alloy (HSLA) steel through electroless deposition processing. The concentrations of 0.25, 0.50 and 1.0 g/L TNPs were dispersed in the electroless bath, to obtain NiP-TNPs nanocomposite coatings comprising different Ti contents. Further, the effect of TNPs on the structural, mechanical, corrosion, and heat treatment performance of NiP coatings was thoroughly studied to illustrate the role of TNPs into the NiP matrix. Field emission scanning electron microscope (FESEM) and energy dispersive spectroscopy (EDX) results confirm the successful incorporation of TNPs into the NiP matrix. A substantial improvement in the mechanical response of the NiP matrix was noticed with an increasing amount of TNPs, which reached to its ultimate values (hardness 675 Hv, modulus of elasticity 18.26 GPa, and stiffness 9.02 kN/m) at NiP-0.5TNPs coatings composition. Likewise, the electrochemical impedance spectroscopy measurements confirmed a tremendous increase in the corrosion inhibition efficiency of the NiP coatings with an increasing amount of TNPs, reaching ~96.4% at a composition of NiP-0.5TNPs. In addition, the NiP-TNPs nanocomposite coatings also unveiled better performance after heat treatment than NiP coatings, due to the presence of TNPs into the NiP matrix and the formation of more stable (heat resistant) phases, such as Ni3P, Ni3Ti, NiO, etc., during the subsequent processing.

Electrochemical and thermodynamic study on the corrosion performance of API X120 steel in 3.5% NaCl solution.

The present work studied the effect of temperature on the corrosion behavior of API X120 steel in a saline solution saturated with CO2 in absence and presence of polyethyleneimine (PEI) as an environmentally safe green inhibitor. The effect of PEI on the corrosion behavior of API X120 steel was investigated using destructive and non-destructive electrochemical techniques. The overall results revealed that PEI significantly decreases the corrosion rate of API X120 steel with inhibition efficiency of 94% at a concentration of 100 µmol L-1. The adsorption isotherm, activation energy and the thermodynamic parameters were deduced from the electrochemical results. It is revealed that the adsorption of PEI on API X120 steel surface follows Langmuir adsorption isotherm adopting a Physi-chemisorption mechanism. Finally, the samples were characterized using scanning electron microscopy (SEM) and atomic force microscopy (AFM) techniques to elucidate the effect of aggressiveness of corrosive media on the surface morphology and the corrosion performance of API X120 steel. The surface topography result indicates that the API X120 steel interface in PEI presence is smoother than CO2 with Cl- ions or Cl- ions only. This is attributed to the compact protective film limits the aggressive ions transfer towards the metallic surface and reduces the corrosion rate. Moreover, PEI inhibition mechanism is based on its CO2 capturing ability and the PEI adsorption on the steel surface beside the siderite layer which give the PEI molecules the ability to reduce the scale formation and increase the corrosion protection due to capturing the CO2 from the brine solution.

Investigations of Structural Requirements for BRD4 Inhibitors through Ligand- and Structure-Based 3D QSAR Approaches.

The bromodomain containing protein 4 (BRD4) recognizes acetylated histone proteins and plays numerous roles in the progression of a wide range of cancers, due to which it is under intense investigation as a novel anti-cancer drug target. In the present study, we performed three-dimensional quantitative structure activity relationship (3D-QSAR) molecular modeling on a series of 60 inhibitors of BRD4 protein using ligand- and structure-based alignment and different partial charges assignment methods by employing comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) approaches. The developed models were validated using various statistical methods, including non-cross validated correlation coefficient (r²), leave-one-out (LOO) cross validated correlation coefficient (q²), bootstrapping, and Fisher's randomization test. The highly reliable and predictive CoMFA (q² = 0.569, r² = 0.979) and CoMSIA (q² = 0.500, r² = 0.982) models were obtained from a structure-based 3D-QSAR approach using Merck molecular force field (MMFF94). The best models demonstrate that electrostatic and steric fields play an important role in the biological activities of these compounds. Hence, based on the contour maps information, new compounds were designed, and their binding modes were elucidated in BRD4 protein's active site. Further, the activities and physicochemical properties of the designed molecules were also predicted using the best 3D-QSAR models. We believe that predicted models will help us to understand the structural requirements of BRD4 protein inhibitors that belong to quinolinone and quinazolinone classes for the designing of better active compounds.

Differences in structural elements of Bcr-Abl oncoprotein isoforms in Chronic Myelogenous Leukemia.

in silico modeling, using Psipred and ExPASy servers was employed to determine the structural elements of Bcr-Abl oncoprotein (p210(BCR-ABL)) isoforms, b2a2 and b3a2, expressed in Chronic Myelogenous Leukemia (CML). Both these proteins are tyrosine kinases having masses of 210-kDa and differing only by 25 amino acids coded by the b3 exonand an amino acidsubstitution (Glu903Asp). The secondary structure elements of the two proteins show differences in five α-helices and nine ß-strands which relates to differences in the SH3, SH2, SH1 and DNA-binding domains. These differences can result in different roles played by the two isoforms in mediating signal transduction during the course of CML.

The prevalence of HBV infection in the cohort of IDPs of war against terrorism in Malakand Division of Northern Pakistan.

BACKGROUND: Hepatitis B is an important public health problem in the Pakistani population and is the major cause of chronic hepatitis, cirrhosis, fibrosis and hepatocellular carcinoma. High prevalence of HBV infections has been observed especially in areas of low economic status. In spite of effective immunization programs, no significant change has been observed in the epidemiology of HBV in the rural areas of Pakistan (~67.5% of the total population) mainly due to lack of interest from government authorities and poor hygienic measures. The current study was aimed at estimating the prevalence and risk factors associated with HBV infection within internally displaced persons (IDPs) due to war against terrorism in the Malakand Division of Northern Pakistan. METHODS: Blood samples from 950 IDPs suspected with HBV infection (including both males and females) were collected and processed with commercial ELISA kits for HBsAg, Anti HBs, HBeAg, Anti HBe antibodies. The samples positive by ELISA were confirmed for HBV DNA by real-time PCR analysis. RESULTS: The overall prevalence of HBV observed was 21.05% of which 78.5% were males and 21.5% were females. Most confirmed HBV patients belong to the Malakand and Dir (lower) district. High-risk of infection was found in the older subjects 29.13% (46-60 years), while a lower incidence (11.97%) was observed in children aged <15 years. Lack of awareness, socioecomic conditions, sexual activities and sharing of razor blades, syringes and tattooing needles were the most common risk factors of HBV infection observed during the cohort of patients. CONCLUSION: The present study, revealed for the first time a high degree of prevalence of HBV infection in rural areas of Northern Pakistan. The noticed prevalence is gender- and age-dependent that might be due to their high exposures to the common risk factors. To avoid the transmission of HBV infection proper awareness about the possible risk factors and extension of immunization to the rural areas are recommended.